Regulation of peroxisome proliferator-activated receptor-alpha mRNA in rat liver.
Regulation of peroxisome proliferator-activated receptor-alpha mRNA in rat liver.
复制标题
大鼠肝脏中过氧化物酶体增殖物激活受体-α mRNA 的调节。
DOI：
10.1006/abbi.1996.0077
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
VandenHeuvel,JP
中科院分区：
文献类型：
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作者：
Sterchele,PF;Sun,H;Peterson,RE;VandenHeuvel,JP
啮齿类动物肝脏中化学诱导的过氧化物酶体增殖被认为是通过激活类固醇激素受体超家族成员过氧化物酶体增殖物激活受体（PPARs）而发生的。在本研究中，检测了主要肝脏亚型PPARα的表达，并与酰基辅酶A氧化酶（ACO）的表达进行了比较，ACO是过氧化物酶体增殖的标志物，也是通过PPARs调控的基因的原型。尽管过氧化物酶体增殖剂全氟癸酸（PFDA）在体内对两种mRNA均有诱导作用，但剂量反应和时间过程表明，PPARα和ACO的控制并不相似。大鼠肝脏中ACO的信使RNA水平迅速升高，并在PFDA给药后7天内下降，而PPARα mRNA升高较慢，并在此期间保持升高。此外，PFDA给药大鼠中的PPARα mRNA蓄积似乎主要是由于摄食量不足，因为配对喂养和完全热量限制导致该信使RNA浓度大幅增加。体内细胞核连续实验表明，与ACO不同，PFDA和热量限制导致了PPARα mRNA的积累，这不能仅仅用转录激活来解释。这些数据表明，PPARα mRNA积累具有非常小的过氧化物酶体增殖物依赖性成分，可能涉及其他因素。以大鼠肝癌细胞系为研究对象，探讨过氧化物酶体增殖物对过氧化物酶体增殖物激活受体α（PPARα）mRNA表达的直接影响。在大鼠肝癌细胞系FaO中，经PFDA或原型过氧化物酶体增殖剂Wy 14，643处理后，PPARα和ACO mRNA水平迅速升高。在该细胞系中，PPARα mRNA水平不受胰高血糖素或胰岛素的影响，此外，该细胞系中的过氧化物酶体增殖物还被油酸和地塞米松诱导。后一种处理对PPARα mRNA积累的影响最大，而对ACO mRNA的影响最小。在Wy 14，643之前用放线菌素D处理FaO细胞可消除ACO和PPARα mRNA的积累，表明过氧化物酶体增殖反应中必须有转录成分。因此，尽管PPARα对过氧化物酶体增殖物有反应，并且在细胞培养中观察到直接作用，但体内mRNA积累主要是转录后的，内源性调节因子如糖皮质激素可能在该类固醇激素受体的组织和发育特异性表达中起关键作用。
Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferator-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPARα was examined and compared to that of acyl-CoA oxidase (ACO), a marker for peroxisome proliferation and a prototype for genes regulated via PPARs. Despite the induction of both mRNA speciesin vivoby the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPARα and ACO are not controlled similarly. Messenger RNA levels for ACO increased rapidly in rat liver and declined over the subsequent 7 days following PFDA administration, while PPARα mRNA increased slower and remained elevated over this period. In addition, PPARα mRNA accumulation in PFDA-treated rats appears to be due primarily to hypophagia as pair feeding and complete caloric restriction result in a large increase in the concentration of this messenger RNA. Nuclear run-on experimentsin vivosuggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPARα mRNA which cannot be explained solely by transcriptional activation. These data indicate that PPARα mRNA accumulation has a very small peroxisome proliferator-dependent component and that other factors may be involved. A rat hepatoma cell line was examined to determine the direct effect of peroxisome proliferators on PPARα mRNA. PPARα and ACO mRNA levels were increased rapidly in the rat hepatoma cell line FaO after treatment with PFDA or the prototypical peroxisome proliferator Wy 14,643. In this cell line, PPARα mRNA levels are not affected by glucagon or insulin and in addition to peroxisome proliferators are induced in this cell line by oleic acid and dexamethasone. The latter treatment had the greatest effect on PPARα mRNA accumulation while having a minimal effect on ACO mRNA. Treatment of FaO cells with actinomycin D prior to Wy 14,643 abolished ACO and PPARα mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPARα is responsive to peroxisome proliferators and direct effects are observed in cell culture, mRNA accumulationin vivois predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.